Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA.
Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
Neuron. 2020 May 6;106(3):404-420.e8. doi: 10.1016/j.neuron.2020.01.042. Epub 2020 Mar 4.
De novo germline mutations in the RNA helicase DDX3X account for 1%-3% of unexplained intellectual disability (ID) cases in females and are associated with autism, brain malformations, and epilepsy. Yet, the developmental and molecular mechanisms by which DDX3X mutations impair brain function are unknown. Here, we use human and mouse genetics and cell biological and biochemical approaches to elucidate mechanisms by which pathogenic DDX3X variants disrupt brain development. We report the largest clinical cohort to date with DDX3X mutations (n = 107), demonstrating a striking correlation between recurrent dominant missense mutations, polymicrogyria, and the most severe clinical outcomes. We show that Ddx3x controls cortical development by regulating neuron generation. Severe DDX3X missense mutations profoundly disrupt RNA helicase activity, induce ectopic RNA-protein granules in neural progenitors and neurons, and impair translation. Together, these results uncover key mechanisms underlying DDX3X syndrome and highlight aberrant RNA metabolism in the pathogenesis of neurodevelopmental disease.
DDX3X 核糖核酸解旋酶的新生种系突变占女性不明原因智力障碍 (ID) 病例的 1%-3%，与自闭症、脑畸形和癫痫有关。然而，DDX3X 突变损害大脑功能的发育和分子机制尚不清楚。在这里，我们使用人类和小鼠遗传学以及细胞生物学和生物化学方法来阐明致病性 DDX3X 变异破坏大脑发育的机制。我们报告了迄今为止最大的 DDX3X 突变临床队列（n=107），表明反复出现的显性错义突变、多小脑回与最严重的临床结局之间存在显著相关性。我们表明，Ddx3x 通过调节神经元生成来控制皮质发育。严重的 DDX3X 错义突变会严重破坏 RNA 解旋酶活性，在神经祖细胞和神经元中诱导异位 RNA-蛋白颗粒，并损害翻译。总之，这些结果揭示了 DDX3X 综合征的关键机制，并强调了神经发育性疾病发病机制中异常的 RNA 代谢。
